Vision is the most important of the senses, and diseases affecting visual function, such as reduced vision or blindness are important physical disabilities. In particular, it is expected that diseases affecting visual function will increase with age as an anticipated problem related to an aging society. In treating a patient whose daily life has been hindered, the importance of improving the quality of life (QOL) of the patient has been recently proposed. In ophthalmologic disease, improving and maintaining visual function are essential elements for improving QOL, hence establishing a therapy for achieving this is an exigency.
Serious reduced visual acuity or blindness can be caused by various factors, and some direct factors are chorioretinopathy such as retinal circulatory obstruction, inflammation, atrophy, and retinal detachment. Therapies adopted for these diseases include certain drug therapies, photocoagulation using laser, and vitreous surgery; however the performance of these has not been satisfactory, and thus other therapies are eagerly awaited. Although drug therapies have some worthy advantages, that is, reduced invasiveness and ease of administration compared with photocoagulation and vitreous surgery, which are inevitably invasive, only a few useful drugs are currently available.
On the other hand, progress of recent basic and clinical studies has clarified pathologically chorioretinopathy, that is, impairment of nerve fiber and obstruction of retinal circulation, and morbidity and pathology of the retinal pigment epithelium, as well as morbidity of the visual cells in the retina.
Among them, it is known that the occurrence of retinal edema directly results in visual loss, and the following mechanism has been proposed. The retina has blood-retinal barriers composed of tight junctions of endothelial cells of a retinal capillary and epithelial cells of the retinal pigment. These inner and outer blood-retinal barriers selectively regulate the transport of materials and water from blood to extracellular cavities of nerve cells. If these barriers are injured by any occasion, blood and exudate will deflux to the extracellular cavities of the retina. The defluxed water and the like are egested by a pumping effect of the retinal pigment of epithelial cells, vascular endothelial cells, and Muller's cells. If they are defluxed in amounts larger than the pumping capacity they are stored in the exterior of the cells causing the retinal edema.
The retina has a thin region consisting of only an outer nuclear layer, which is called a fovea, at the region of the macula, and an inner nuclear layer and a ganglion cell layer lie on the periphery. A non-vascular region lies in the center, and the retina has a larger thickness on its periphery. The central photoreceptor cells have long axons connecting with the cells in the inner nuclear layer. The layer of the axons of the photoreceptor cells corresponds to Henle's fiber layer lying in the outermost layer of the outer plexiform layer.
The Henle's fiber layer is a convergence of photoreceptor cell axons radially distributing from the fovea. In the reticular layers at the other portions, axons intertwine with each other in various directions, whereas in the macula section an interstitial gap readily becomes larger when the exudate is stored, and the increased gap causes further inflow of the exudate. Such storing of a large amount of exudate in the macula section in the retina is called cystoid macular edema (CME).
The macula section is the most important section for sight, and prolonged edema causes progressive obstruction of nerve fibers and visual cells (cell death), atrophy of the retinal pigment epithelium, and thus external obstruction of visual function. If the inner limiting membrane of the cyst including the fovea breaks, a lamellar macular hole will be formed. Further progression of the symptoms may cause societal blindness.
Cystoid macular edema is said to be caused by all the diseases of the diffuse retinal edema, and originates from retinopathy or choroidopathy. These are caused by surgery, vascular morbidity, inflammation, degenerative morbidity, or drugs. In particular, these are frequently caused by diabetic retinopathy, branch retinal vein occlusion, central retinal vein occlusion, intraocular surgery, intraocular inflammation, and choroidal neovas culorization. In recent years, cataract surgery has been frequently performed with the spread of intraocular lens. Miyake reviewed 246 eyes of 196 total lens enucleations in senile cataract of people of sixty or over not having noticeable complication during operation. According to fluorescein angiography three to seven weeks after the operation, 23% of people did not have cystoid macular edema whereas 52% of people had cystoid macular edema. Thus, frequency of cystoid macular edema is significantly high and is expected to increase further with an increase in the aged population.
Some possible development mechanisms have been suggested, although many unclarified matters still remain. Suggested mechanisms for edema include, for example, an increase in retinal blood flow caused by an increase in hydrostatic pressure at the venous end or an increase in diameter of capillaries, breakdown of the retinal blood barrier, an increase in production of a permeability increasing factor such as prostaglandin, and vitreous traction. A satisfactory conclusion has, however, not been drawn regarding the relationship between the development mechanisms and the original disease.
Although the cystoid macular edema is a significant factor in reduced visual acuity, its therapy has not been established. Current therapies are as follows.
Drugs for drug therapies are, for example, prostaglandin biosynthesis inhibitors, steroids, and carbonic anhydrase inhibitors. Instillation of prostaglandin biosynthesis inhibitors is said to be effective for initial cystoid macular edema, but not effective for chronic cystoid macular edema. Regarding steroids, oral administration and administration into the Tenon's capsule have been tried; however, there are differences in effect between the reports, and recurrence is recognized. Further, cataract and glaucoma are complications, hence unstable results have been obtained. Although administration of carbonic anhydrase inhibitors improves the acuity, it has many problems, that is, it decreases when the administration is suspended, exacerbation is recognized during prolonged administration, and the inhibitors have strong general adverse effects.
Other therapies include, for example, photocoagulation, hyperbaric oxygen therapies, and surgical therapies. Regarding photocoagulation, there are some reports on suppression of symptoms, whereas there are some cases without suppression of symptom; hence, their effects have not yet been confirmed. Hyperbaric oxygen therapies have many problems, that is, they involve recurrence, the patient must have plenty of load in the therapy, and the facility is limited. Since satisfactory surgical therapies are not established, they cannot be generally performed.
With the recent progress in the understanding of cell biology, a vascular endothelial growth factor (VEGF) has been found as a vascular permeability factor, and interleukin(IL)-1, IL-6, IL-8, a tumor necrosis factor (TNF), a granulocyte-macrophage colony stimulating factor (GM-CSF), a macrophage colony stimulating factor (M-CSF), monocyte chemotactic protein (MCP), a basic fibroblast growth factor (bFGF), and a tumor transforming growth factor-.beta. (TGF-.beta.) have been found as factors that are produced by or participate in retinal pigment of epithelial cells; however, clinical trials of application of anti-VEGF antibody and TGF-.beta. to humans have only just begun, and effects of retinal edema and particularly cystoid macular edema have not been clarified.
As described above, although retinal edema and particularly cystoid macular edema are severe factors causing reduced visual acuity, satisfactory therapies including drug therapies have not been established. Accordingly, the establishment of a novel therapy or prophylactic treatment has been eagerly awaited.
It is an object of the present invention to provide a novel remedy which is useful, from industrial or medical point of view, for therapy or prophylactic treatment of retinal edema, and particularly cystoid macular edema not having established therapy or drug therapy.